Titration dosing regimen for controlled release tramadol

ABSTRACT

A titration dosing regimen for the administration of controlled release tramadol analgesic to patients. The titration dosing regimen provides a significant reduction in the occurrence of adverse effects from the introduction of controlled released tramadol dosing, thus increasing patient compliance and medication tolerability.

1. CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. application Ser.No. 10/800,254, filed Mar. 10, 2004, now U.S. Pat. No. 7,413,749, whichclaims the benefit of U.S. Provisional Application No. 60/453,848, filedMar. 11, 2003, the disclosures of which are incorporated by referenceherein in their entireties.

2. FIELD OF THE INVENTION

This invention relates to a titration dosing regimen for theadministration of controlled release dosage forms of tramadol topatients. The novel titration dosing regimen reduces the occurrence ofadverse effects which often result from beginning administration of acontrolled release tramadol dosage at the mean level required foradequate analgesia, and thus, greatly reduces the number of patientsthat discontinue administration of tramadol due to the adverse effectsexperienced during the introductory dosage period. Consequently, thistitration dosing regimen increases the therapeutic benefit of controlledrelease tramadol by minimizing adverse effects.

3. BACKGROUND OF THE INVENTION

Tramadol, which has the chemical name(+/−)-trans-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol,is a centrally acting synthetic opioid analgesic that is effective forthe management of moderate to severe pain. After oral administration,tramadol is rapidly absorbed and metabolized into the pharmacologicallyactive metabolite mono-O-desmethyltramadol. Conventional releasepreparations in the form of capsules, drops and suppositories containingtramadol have been commercially available for many years for use in thetreatment of moderate to severe pain.

The prior art addresses the titration dosage regimen for immediaterelease tramadol. For example, U.S. Pat. No. 6,339,105 discloses adosage regimen for immediate release tramadol including about 25 mg ondays 1 to 3; 50 mg on days 4 to 6; 75 mg on days 7 to 9; 100 mg on days10 to 12; 150 mg on days 13 to 15 and 200 mg on days 16 to 28. Alsodisclosed therein is a dosage regimen for immediate release tramadolincluding 25 mg q.d. on days 1 to 3; 25 mg b.i.d. on days 4-6, 25 mgt.i.d. on days 7 to 9; 25 mg q.i.d. on days 10 to 12; and 50 mg t.i.d.on days 13 to 28. The dosing of a controlled release form is notaddressed in U.S. Pat. No. 6,339,105.

Controlled release tramadol is known to elicit adverse effects,including nausea, vomiting, sleepiness, dizziness, itchiness, sedation,dry mouth, sweating and constipation.

Thus, a need exists for the development of an advantageous dosingregimen for a controlled release dosage form of tramadol. Morespecifically, there exists a need for a dosage regimen for a controlledrelease tramadol which significantly reduces the occurrence of andconcomitant severity of adverse tramadol elicited side effects, andthus, reduces potential discontinuation by patients due to these effectsand increases the number of patients who may successfully be treated.

4. DEFINITIONS

The term “controlled release” is defined for purposes of the presentinvention as the release of the drug (i.e., tramadol) in vitro over aperiod of time about 12 hours or more, more preferably for periods ofabout 24 hours or longer. The term “controlled release” is deemed toencompass the term “prolonged release” as that term is used by theCommittee on Proprietary Medicinal Products (“CPMP”).

Unless specified to the contrary, any reference to any pharmaceuticalcompound, such as tramadol, throughout this disclosure includes not onlythat pharmaceutical compound, i.e., the so-called free form of thatcompound, but also pharmaceutically acceptable derivatives,pharmaceutically acceptable salts of that compound, base forms of thatcompound, optical isomers of that compound, stereoisomers of thatcompound, and mixtures of any of the foregoing.

The phrase “pharmaceutically acceptable salt,” as used herein, is a saltformed from an acid and the basic group of an active agent or an adverseagent. Generally, examples of such salts include, but are not limited,to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide,nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate,salicylate, acid citrate, tartrate, oleate, tannate, pantothenate,bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate,gluconate, glucaronate, saccharate, formate, benzoate, glutamate,methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate,glubionate and pamoate (i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. The term“pharmaceutically acceptable salt” also refers to a salt prepared froman active agent or an adverse agent having an acidic functional group,such as a carboxylic acid or sulfonic acid functional group, and apharmaceutically acceptable inorganic or organic base. Generally,examples of such bases include, but are not limited to, hydroxides ofalkali metals such as sodium, potassium, and lithium; hydroxides ofalkaline earth metal such as calcium and magnesium; hydroxides of othermetals, such as aluminum and zinc; ammonia, and organic amines, such asunsubstituted or hydroxy-substituted mono-, di-, or trialkylamines;dicyclohexylamine; tributyl amine; pyridine; N-methyl,N-ethylamine;diethylamine; triethylamine; mono-, bis-, or tris-(2-hydroxy-lower alkylamines), such as mono-, bis-, or tris-(2-hydroxyethyl)amine,2-hydroxy-tert-butylamine, or tris-(hydroxymethyl)methylamine,N,N,-di-lower alkyl-N-(hydroxy lower alkyl)-amines, such asN,N,-dimethyl-N-(2-hydroxyethyl)amine, or tri-(2-hydroxyethyl)amine;N-methyl-D-glucamine; and amino acids such as arginine, lysine, and thelike.

The term “base form” as used herein, e.g., for tramadol, refers to asalt prepared from tramadol having an acidic functional group, such as acarboxylic acid or sulfonic acid functional group, and apharmaceutically acceptable inorganic or organic base. Suitable basesinclude, but are not limited to, hydroxides of alkali metals such assodium, potassium, and lithium; hydroxides of alkaline earth metal suchas calcium and magnesium; hydroxides of other metals, such as aluminumand zinc; ammonia, and organic amines, such as unsubstituted orhydroxy-substituted mono-, di-, or trialkylamines; dicyclohexylamine;tributyl amine; pyridine; N-methyl, N-ethylamine; diethylamine;triethylamine; mono-, bis-, or tris-(2-hydroxy-lower alkyl amines), suchas mono-, bis-, or tris-(2-hydroxyethyl)amine,2-hydroxy-tert-butylamine, or tris-(hydroxymethyl)methylamine,N,N,-di-lower alkyl-N-(hydroxy lower alkyl)-amines, such asN,N,-dimethyl-N-(2-hydroxyethyl)amine, or tri-(2-hydroxyethyl)amine;N-methyl-D-glucamine; and amino acids such as arginine, lysine, and thelike.

The term “tramadol-like side effects” is defined for purposes of thepresent invention as including, but not limited to, nausea, vomiting,sleepiness, dizziness, itchiness, dry mouth, and constipation.

The term “distractor side effects” is defined for purposes of thepresent invention as including, but not limited to, toothache, cough,abdominal pain, joint pain, blurry vision, fever, and dyspepsia.

The term “statistically significant” is defined for purposes of thepresent invention as P<0.04999, where P values are derived frompair-wise comparisons of treatment groups versus placebo from theanalysis of variance using Fischer's LSD.

The term “THCR” is defined for purposes of the present invention astramadol hydrochloride controlled release oral dosage form.

The term “substantially,” as used herein, when modifying an adjective oradjective phrase immediately succeeding it, should be understood to meanthat adjective or adjective phrase applies to at least about a 95%level, preferably to at least about a 98% level, more preferably to atleast a 99% level, for example to at least about a 99.9% level, withrespect to the noun or pronoun that the adjective or adjective phrasemodifies.

The term “curing” is defined for purposes of the present invention asthe heat treatment of the dosage form (or intermediate product) forpurposes of obtaining a stabilized final oral pharmaceutical controlledrelease dosage form. When the formulations of the invention incorporatea polymer as part or all of the hydrophobic retarding agent, it will beappreciated by those skilled in the art that a heat treatment causes acuring effect and that the polymer possibly cross-links with itself intoa more stable state. When the formulations of the invention do notincorporate a polymer but rather include a hydrophobic material such as,e.g., hydrogenated vegetable oil or stearyl alcohol, one skilled in theart will appreciate that the heat treatment is more akin to an annealingof the formulation rather than a curing of the polymer. However, forpurposes of the present invention, the use of the term “curing” isdeemed to encompass both curing and/or annealing.

The terms “stable dissolution profile” and “curing endpoint” are definedfor purposes of the present invention as meaning that the cured soliddosage form (e.g., tablet) reproducibly provides a release of the activeagent (e.g., tramadol) when placed in an environment of use which isunchanged, even after exposing the cured formulation to acceleratedstorage conditions. Those skilled in the art will recognize that by“unchanged” it is meant that any change in the release of the activeagent from the cured formulation would be deemed insignificant in termsof the desired effect. For pharmaceutical formulations, stability isdetermined by, e.g., a regulatory agency such as the Food & DrugAdministration (“FDA”) in the U.S., or the CPMP in Europe, for thepurpose of according an expiration date for the formulation.

By the phrase “accelerated storage conditions” it is meant, e.g.,storage conditions of elevated temperature and/or elevated relativehumidity. Preferably, the phrase “accelerated storage conditions” refersto storage conditions to which the final drug formulation is subjectedfor the purpose of obtaining regulatory approval (e.g., FDA approval inthe U.S.) and an expiration date.

The term “expiration date” is defined for purposes of the presentinvention as the date designating the time during which a batch of theproduct (e.g., the cured, coated substrate) is expected to remain withinspecification if stored under defined conditions, and after which itshould not be used.

The term “band range” for purposes of the present invention is definedas the difference in in vitro dissolution measurements of the controlledrelease formulations when comparing the dissolution profile (curve)obtained by the formulation upon completion of the manufacturing of thecoated product (prior to storage) and the dissolution profile obtainedafter the coated product is exposed to accelerated storage conditions,expressed as the change in percent of the active agent released from thecoated product at any dissolution time point along the dissolutioncurves.

The term “W 50” is defined as the width of the curve of the graphicalrepresentation of the in vivo blood plasma concentration of tramadol inng/ml versus the time elapsed after administration in hours.

5. SUMMARY OF THE INVENTION

In one embodiment, the present invention includes a dosage regimen foradministering tramadol to a patient comprising administering: about 75mg to about 125 mg of tramadol in a controlled release dosage formonce-a-day, or q.d., for about 4 to about 10 days; then about 175 mg toabout 225 mg of tramadol in a controlled release dosage form once-a-dayfor about 4 to about 10 days; then about 275 mg to about 325 mg oftramadol in a controlled release dosage form once-a-day for at least 1day and optionally thereafter.

In another embodiment, the present invention includes a titration dosageregimen comprising administering to one in need thereof 100 mg q.d., oronce-a-day, of controlled release tramadol for about seven consecutivedays (days 1-7), followed by 200 mg q.d. of controlled released tramadoladministered for about the next seven consecutive days (days 8-14), andthen 300 mg q.d. of controlled released tramadol administered on aboutday 15 and optionally thereafter.

The present invention includes titration dosing regimen which eithercontinue to administer controlled release tramadol at a dosage of 300 mgq.d. on days 16 and for a period thereafter, or which increase, decreaseor cease the administration of controlled release tramadol to thepatient after day 15. For example, the invention includes administering300 mg q.d. of controlled release tramadol on days 16 through 21.

One embodiment of the invention includes a kit for the administration ofa dosage regimen of tramadol comprising:

instructions to administer the following amounts of tramadol incontrolled release oral dosage forms according to the following dosageregimen:

100 mg of tramadol once-a-day on days 1 through 7;

200 mg of tramadol once-a-day on days 8 through 14; and

300 mg of tramadol once-a-day on days 15 through 21,

and optionally thereafter; and

a sufficient quantity of controlled release oral dosage forms oftramadol to administer tramadol according to the dosage regimen.

Additional embodiments include a dosage regimen for administeringtramadol to a patient comprising administering: about 175 mg to about225 mg of tramadol in a controlled release dosage form once-a-day forabout 4 to about 10 days; then about 275 mg to about 325 mg of tramadolin a controlled release dosage form once-a-day for at least 1 day andoptionally thereafter. For example, the invention includes furtheradministering about 275 mg to about 325 mg for about 6 days to about 14days, and optionally thereafter.

In another embodiment, the controlled release tramadol titration dosingregimen of the present invention comprises administering 200 mg q.d.controlled release tramadol on days 1 to 7; and 300 mg q.d. on day 8 andoptionally for a time thereafter. For example, the present inventionincludes a titration dosing regimen which further comprisesadministering controlled release tramadol at a dosage of 300 mg q.d. ondays 8 through 21. The present invention also includes administering 300mg q.d. of controlled release tramadol for a longer or shorter period oftime after day 8, as well as either increasing, decreasing and/orceasing the dosage of controlled release tramadol after day 8.

Another embodiment of the invention includes a kit for theadministration of a dosage regimen of tramadol comprising:

instructions to administer the following amounts of tramadol incontrolled release oral dosage forms according to the following dosageregimen:

200 mg of tramadol once-a-day on days 1 through 7; and

300 mg of tramadol once-a-day on days 8 through 15,

and optionally thereafter; and

a sufficient quantity of controlled release oral dosage forms oftramadol to administer tramadol according to the dosage regimen.

It has been discovered that, while reaching the most commonly prescribeddose of 300 mg of tramadol, the titration dosage regimen of controlledrelease tramadol according to the present invention often results in asignificant reduction of adverse side effects and significantly bettertolerance than starting doses of 300 mg q.d. on day 1.

6. DETAILED DESCRIPTION OF THE INVENTION

In certain embodiments, the present invention includes a dosage regimenfor administering tramadol to a patient comprising administering about75 mg to about 125 mg of tramadol in a controlled release dosage formonce-a-day for about 4 to about 10 days; then about 175 mg to about 225mg of tramadol in a controlled release dosage form once-a-day for about4 to about 10 days; then about 275 mg to about 325 mg of tramadol in acontrolled release dosage form once-a-day for at least 1 day andoptionally thereafter.

In one embodiment, the regimen of the present invention is a 21 daytitration, whereby 100 mg q.d. controlled release tramadol isadministered on days 1 to 7. The dosage of controlled release tramadolis increased to 200 mg q.d. for days 8-14, and then increased again to300 mg q.d. controlled release tramadol during days 15-21.

An alternative embodiment of the present invention comprises a titrationdosing regimen for controlled release tramadol comprising administeringto a patient in need thereof 100 mg q.d. controlled release tramadol ondays 1 through 7; 200 mg q.d. controlled release tramadol on days 8through 14; and 300 mg q.d. controlled release tramadol on day 15.Thereafter, the administration of tramadol to the patient may be eithercontinued at the 300 mg dosage level, increased, decreased or terminatedin accordance with the patient's needs.

In another embodiment, the present invention includes a kit for theadministration of a dosage regimen of tramadol comprising:

instructions to administer the following amounts of tramadol incontrolled release oral dosage forms according to the following dosageregimen:

100 mg of tramadol once-a-day on days 1 through 7;

200 mg of tramadol once-a-day on days 8 through 14; and

300 mg of tramadol once-a-day on days 15 through 21,

and optionally thereafter; and

a sufficient quantity of controlled release oral dosage forms oftramadol to administer tramadol according to the dosage regimen.

The kit may preferably consist of a plurality of oral dosage formscontaining amounts of tramadol selected from the group consisting of 100mg, 200 mg and 300 mg.

In other embodiments, the present invention includes a dosage regimenfor administering tramadol to a patient comprising administering about175 mg to about 225 mg of tramadol in a controlled release dosage formonce-a-day for about 4 to about 10 days; then about 275 mg to about 325mg of tramadol in a controlled release dosage form once-a-day for atleast 1 day and optionally thereafter.

In another embodiment, the present invention includes an initialtitration dosage regimen for controlled release tramadol comprisingadministering to a patient in need thereof 200 mg q.d. of controlledrelease tramadol on days 1 through 7 and 300 mg q.d. of controlledrelease tramadol on day 8. Thereafter, the dosage level may eitherremain at 300 mg q.d. of controlled release tramadol or may be eitherincreased, decreased or ceased depending upon the needs of the patient.

In another embodiment, the present invention includes a kit for theadministration of a dosage regimen of tramadol comprising:

instructions to administer the following amounts of tramadol incontrolled release oral dosage forms according to the following dosageregimen:

200 mg of tramadol once-a-day on days 1 through 7; and

300 mg of tramadol once-a-day on days 8 through 15,

and optionally thereafter; and

a sufficient quantity of controlled release oral dosage forms oftramadol to administer tramadol according to the dosage regimen.

The kit may preferably consist of a plurality of oral dosage formscontaining amounts of tramadol selected from the group consisting of 100mg, 200 mg and 300 mg.

The dosage regimen of the present invention may be practiced byadministering any controlled release dosage form containing tramadol.However, in certain embodiments, the controlled release dosage form isan oral dosage form such as, for example, a tablet or capsule.

The tramadol may be present in the controlled release dosage form in anypharmaceutically acceptable form. The controlled release dosage formprovides an in vitro release of tramadol for at least about 12 hours ormore. In certain embodiments, the controlled release dosage formprovides an in vitro release of tramadol for about 24 hours or longer.

6.1 Controlled Release Tramadol Dosage Forms

The present invention encompasses titration dosage regimen foradministering any controlled release dosage form of tramadol. Examplesof suitable controlled release tramadol oral dosage forms may be foundin U.S. Pat. Nos. 6,326,027 and 6,306,438, the disclosures of which areexpressly incorporated herein in their entirety. The following detaileddescription sets forth exemplary formulations and methods of manufacturefor oral THCR which may be administered in accordance with the presentinvention.

For example, in order to obtain a controlled release tramadol oraldosage form, the tramadol may be homogeneously combined with asufficient amount of one or more hydrophobic (release-retardant)material(s), such as a wax or a wax-like material (“wax-likesubstance”).

The hydrophobic material(s) used in such controlled release tramadolformulations may include, for example, material(s) such as, acrylic ormethacrylic polymers or copolymers, alkylcelluloses, zein, shellac, anatural or synthetic wax or oil, including but not limited to,hydrogenated fats such as hydrogenated vegetable oil, hydrogenatedcastor oil, microcrystalline wax, normal waxes, beeswax, carnauba wax,paraffin, or glyceryl monostearate, and may have a melting point of from45 to 140° C., preferably 50 to 110° C. Ammonio methacrylate copolymersare suitable, for example.

The hydrophobic material(s) may be any pharmaceutically acceptableacrylic polymer, including but not limited to, any of acrylic acid andmethacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethylmethacrylates, cynaoethyl methacrylate, aminoalkyl methacrylatecopolymer, poly(acrylic acid), poly(methacrylic acid), methacrylic acidalkylamide copolymer, poly(methyl methacrylate), poly(methacrylic acid)(anhydride), methyl methacrylate, polymethacrylate, poly(methylmethacrylate), poly(methyl methacrylate) copolymer, polyacrylamide,aminoalkyl methacrylate copolymer, poly(methacrylic acid anhydride), andglycidyl methacrylate copolymers.

The acrylic polymer may also be comprised of one or more ammoniomethacrylate copolymers. Ammonio methacrylate copolymers are well knownin the art, and are fully polymerized copolymers of acrylic andmethacrylic acid esters with a low content of quaternary ammoniumgroups. Examples of such acrylic polymers are acrylic resin lacquerscommercially available from Rohm Pharma under the Tradename Eudragit™.

Alternatively or in addition to the above materials, the wax or wax-likesubstance(s) used in the formulations of the present invention mayinclude fatty alcohols, fatty acid esters, fatty acid glycerides (mono-,di-, and tri-glycerides), higher aliphatic (e.g., C₁₀-C₂₀) acids, higheraliphatic (e.g., C₁₂-C₃₆) alcohols, long chain fatty acids, and mixturesthereof. In certain embodiments, useful water-insoluble wax-likesubstances may be those with a water-solubility that is lower than about1:5,000 (w/w). The higher aliphatic alcohol may be, for example, laurylalcohol, myristyl alcohol or stearyl alcohol.

One particularly suitable controlled release matrix includes one or morealkylcelluloses and one or more C₁₂-C₃₆ aliphatic alcohols. Thealkylcellulose is preferably C₁-C₆ alkyl cellulose, particularlyethylcellulose, and the higher aliphatic alcohol is preferably stearylalcohol.

The release of the active agent from the controlled release formulationcan be further influenced, i.e., adjusted to a desired rate, by theaddition of one or more release-modifying agents into the matrix. Therelease-modifying agents may comprise one or more water-solublehydrophilic polymers in order to modify the release characteristics ofthe formulation. Examples of suitable hydrophilic polymers includecellulose ethers, such as hydroxyalkylcelluloses (e.g.,hydroxypropylmethylcellulose), and carboxyalkylcelluloses, acrylicresins and protein-derived materials. Also, synthetic water-solublepolymers may be used, such as polyvinylpyrrolidone, cross-linkedpolyvinylpyrrolidone, polyethylene oxide, etc., and polysaccharides,e.g., pullulan, dextran, sucrose, glucose, fructose, mannitol, lactose,mannose, galactose, sorbitol and mixtures thereof.

Semipermeable polymers may also be incorporated in the matrix to changethe release characteristics of the formulation. Such semipermeablepolymers include, for example, cellulose acylates, acetates, and othersemipermeable polymers such as those described in U.S. Pat. No.4,285,987, as well as the selectively permeable polymers formed by thecoprecipitation of a polycation and a polyanion as disclosed in U.S.Pat. Nos. 3,173,876; 3,276,586; 3,541,005; 3,541,006 and 3,546,142.

It may be desirable to also add a plasticizer when using certainhydrophobic polymers. Examples of suitable plasticizers forethylcellulose include water insoluble plasticizers such as dibutylcitrate, dibutyl sebacate, diethyl phthalate, triethyl citrate, tributylcitrate, and triacetin, although it is possible that otherwater-insoluble plasticizers (such as acetylated monoglycerides,phthalate esters, castor oil, etc.) may be used. Examples of suitableplasticizers for acrylic polymers include citric acid esters such astriethyl citrate, tributyl citrate, dibutyl phthalate, and possibly1,2-propylene glycol, polyethylene glycols, propylene glycol, diethylphthalate, castor oil, and triacetin, although it is possible that otherwater-insoluble plasticizers (such as acetylated monoglycerides,phthalate esters, castor oil, etc.) may be used. However, controlledrelease tramadol dosage forms can be prepared without the presence of aplasticizer.

In addition to the foregoing, the controlled release tramadolformulations may include pharmaceutically acceptable carriers andexcipients. Specific examples of pharmaceutically acceptable carriersand excipients that may be used to formulate oral dosage forms aredescribed in the Handbook of Pharmaceutical Excipients, AmericanPharmaceutical Association (1986), incorporated by reference herein.Techniques and compositions for making solid oral dosage forms aredescribed in Pharmaceutical Dosage Forms: Tablets (Lieberman, Lachmanand Schwartz, editors) Second Edition, published by Marcel Dekker, Inc.,incorporated by reference herein. Techniques and compositions for makingtablets (compressed and molded), capsules (hard and soft gelatin) andpills are also described in Remington's Pharmaceutical Sciences, (ArthurOsol, editor), 1553-1593 (1980), incorporated by reference herein.Pharmaceutically acceptable ingredients which are conventional in thepharmaceutical art include diluents, lubricants, binders, granulatingaids, colorants, flavorants, surfactants, pH adjusters, anti-adherentsand glidants, e.g., dibutyl sebacate, ammonium hydroxide, oleic acid andcolloidal silica.

The total amount of tramadol in the controlled release dosage form mayvary within wide limits, including, but not limited to from about 20 toabout 80%, preferably from about 40 to about 60%, and most preferablyfrom about 45 to about 55%, by weight. The total amount of hydrophobicmaterial in the controlled release dosage form may also vary widely,including but not limited to, from about 80 to about 20%, by weight.

In one embodiment, the controlled release tramadol dosage form suitedfor once-a-day dosing may have an in vitro release rate corresponding tothe following % rate of tramadol released: from about 0 to about 50%tramadol released after about 1 hour; from about 0 to about 75% tramadolreleased after about 2 hours; from about 10 to about 95% tramadolreleased after about 4 hours; from about 35 to about 100% tramadolreleased after about 8 hours; from about 55 to about 100% tramadolreleased after about 12 hours; from about 70 to about 100% tramadolreleased after about 16 hours; and more than about 90% tramadol releasedafter about 24 hours.

In another embodiment, the controlled release tramadol dosage formsuited for once-a-day dosing may have an in vitro release ratecorresponding to the following % rate of tramadol released: from about 0to about 30% tramadol released after about 1 hour; from about 0 to about40% tramadol released after 2 hours; from about 3 to about 55% tramadolreleased after about 4 hours; from about 10 to about 65% tramadolreleased after about 8 hours; from about 20 to about 75% tramadolreleased after about 12 hours; from about 30 to about 88% tramadolreleased after about 16 hours; from about 50 to about 100% tramadolreleased after about 24 hours; and more than about 80% tramadol releasedafter about 36 hours.

More preferably, a controlled release tramadol dosage form particularlysuited for once-a-day dosing has an in vitro release rate as follows:from about 15 to about 25% tramadol released after about 1 hour; fromabout 25 to about 35% tramadol released after about 2 hours; from about30 to about 45% tramadol released after about 4 hours; from about 40 toabout 60% tramadol released after about 8 hours; from about 55 to about70% tramadol released after about 12 hours; and from about 60 to about75% tramadol released after about 16 hours.

In certain embodiments, the controlled release tramadol dosage formsuitable for once-a-day dosing may have a T_(max) in the range of about3 to about 8 hours, preferably about 4 to about 5 hours and a W₅₀ valuein the range about 10 to about 33 hours.

The in vitro release rates mentioned herein are, except where otherwisespecified, those obtained by measurement using the USP Apparatus 2(Paddle Method) at 100 rpm in pH 6.5 phosphate buffer at 37° C.

The controlled release formulation preferably contains an analgesicallyeffective amount of tramadol, which may conveniently be in the range offrom about 50 to about 300 mg, especially 100, 200 or 300 mg (calculatedas tramadol hydrochloride) per dosage unit.

The controlled release formulations slowly release the tramadol, e.g.,when ingested and exposed to gastric fluids, and then to intestinalfluids. The controlled release profile of the formulations can bealtered, for example, by varying the amount of hydrophobic polymer, byvarying the amount of plasticizer relative to hydrophobic polymer, bythe inclusion of additional ingredients or excipients, by altering themethod of manufacture, etc.

6.2 Manufacture of Controlled Release Tramadol Dosage Form

The present invention includes the dosing of controlled releasetramadol, regardless of the particular formulation or method ofmanufacture of the dosage form. The following exemplary methods ofmanufacturing the controlled release tramadol dosage form are suitable.Additionally, suitable methods of manufacturing the controlled releasetramadol dosage form include those set forth in U.S. Pat. Nos. 6,306,438and 6,326,027, the disclosures of each are expressly incorporated hereinby reference.

One acceptable process for preparing a controlled release preparationfor use in the present invention comprises incorporating tramadol in acontrolled release matrix, for example by

(a) granulating a mixture comprising tramadol or a pharmaceuticallyacceptable salt thereof and one or more alkylcelluloses,

(b) mixing the alkylcellulose containing granules with one or moreC₁₂₋₃₆ aliphatic alcohols; and optionally

(c) shaping and compressing the granules, and film coating, if desired.

Another suitable method for manufacturing the controlled release dosageform is as follows:

(a) granulating a mixture comprising tramadol or a pharmaceuticallyacceptable salt thereof, lactose and one or more alkylcelluloses withone or more C₁₂₋₃₆ aliphatic alcohol; and, optionally,

(b) shaping and compressing the granules, and film coating, if desired.

The controlled release dosage form may also be prepared in the form offilm coated spheroids by

(a) granulating the mixture comprising tramadol or a pharmaceuticallyacceptable salt thereof and a spheronizing agent;

(b) extruding the granulated mixture to give an extrudate;

(c) spheronizing the extrudate until spheroids are formed; and

(d) coating the spheroids with a film coat.

The controlled release dosage form may also be prepared by a processwhich comprises forming a mixture of dry active ingredient and fusiblerelease control materials followed by mechanically working the mixturein a high speed mixer with an energy input sufficient to melt or softenthe fusible material whereby it forms particles with the activeingredient. The resultant particles, after cooling, are suitably sievedto give particles having a size range from about 0.1 to about 3.0 mm inany dimension.

The sustained release dosage form may comprise a capsule filled withcontrolled release particles comprising the active ingredient, ahydrophobic material or diluent and optionally a hydrophillic releasemodifier.

The hydrophilic release modifier may be a water soluble fusiblematerial, such as a polyethylene glycol, and may be a particulatematerial, such as dicalcium phosphate or lactose.

Another acceptable process for the manufacture of a controlled releasetramadol dosage form comprises

(a) mechanically working in a high-speed mixer, a mixture of tramadol inparticulate form and a particulate, hydrophobic material or diluenthaving a melting point from about 35 to about 140° C. and optionally arelease control component comprising a water soluble fusible material,or a particulate soluble or insoluble organic or inorganic material, ata speed and energy input which allows the carrier or diluent to melt orsoften, whereby it forms agglomerates;

(b) breaking down the larger agglomerates to give controlled releaseseeds; and

(c) continuing mechanically working, with optionally a further additionof low percentage of the carrier or diluent; and.

(d) optionally repeating steps (c) and possibly (b) one or more times.

The resulting particles may be sieved to eliminate any over-orundersized material then formed into the desired dosage units by, forexample, encapsulation into hard gelatin capsules containing therequired dose of the active substance or by compressing into tablets.

In this method, all the tramadol may be added in step (a) together witha major portion of the hydrophobic material used.

Stage (a) of the process may be carried out in conventional high speedmixers with a standard stainless steel interior, e.g., a ColletteVactron 75 or equivalent mixer. The mixture may be processed until a bedtemperature about 40° C. or above is achieved and the resulting mixtureacquires a cohesive granular texture, with particle sizes ranging fromabout 1-3 mm to fine powder in the case of non-aggregated originalmaterial. Such material may generally have the appearance ofagglomerates which upon cooling below 40° C. have structural integrityand resistance to crushing between the fingers. At this stage theagglomerates may be of an irregular size, shape and appearance.

The agglomerates are preferably allowed to cool. The temperature towhich it cools is not critical and a temperature in the range roomtemperature to 37° C. may be conveniently used.

The agglomerates are broken down by any suitable means, which willcomminute oversize agglomerates and produce a mixture of powder andsmall particles preferably with a diameter under 2 mm. The particles maybe classified by size by using a Jackson Crockatt granulator with asuitable sized mesh, or a Comil with an appropriate sized screen. A meshsize of 12 has been found adequate.

The classified material is returned to the high speed mixer, andprocessing is continued. It is believed that this leads to agglomerationof the finer particles into particles of uniform size range.

Processing of the classified materials may be continued until thehydrophobic material used begins to soften or melt and optionallyadditional hydrophobic material may then be added. Mixing is continueduntil the mixture has been transformed into particles of the desiredpredetermined size range.

In order to obtain uniform energy input into the ingredients in the highspeed mixer at least part of the energy may be supplied by means ofmicrowave energy. Energy may also be delivered through other means suchas by a heating jacket or via the mixer impeller and chopper blades.

After the particles have been formed they are cooled or allowed to cool,and may then be sieved to remove any cover or undersized material.

The resulting particles may be used to prepare dosage units in the formof e.g. tablets, capsules, multiparticulates or granules in mannersknown per se. The controlled release formulations according to theinvention may conveniently be film coated using any film coatingmaterial conventional in the pharmaceutical art. Preferably an aqueousfilm coating is used.

The granules or tablets may be film-coated according to well knownmethods. For example, the granules may be film-coated and then eitherdivided into unit doses of tramadol (e.g., and placed in a gelatincapsule), or compressed into a tablet. The film coating may beaccomplished prior to or after a curing step.

In other embodiments, the film-coating substantially comprises ahydrophilic polymer and does not affect the rate of release of the drugfrom the formulation. The film-coatings which may be used preferably arecapable of producing a strong, continuous film that is smooth andelegant, capable of supporting pigments and other coating additives,non-toxic, inert, and tack-free.

In certain embodiments, the film-coating may contribute to the releaseproperties of the dosage form. In such cases, the dosage form, e.g.,granules or tablets, may be coated with a sufficient amount ofhydrophobic material to obtain a weight gain level from about 1 to about30 percent. The solvent which is used for the hydrophobic material maybe any pharmaceutically acceptable solvent, including water, methanol,ethanol, methylene chloride and mixtures thereof. It is preferablehowever, that the coatings be based upon aqueous dispersions of thehydrophobic material. The hydrophobic polymer used in such film-coatingsmay comprise, for example, a pharmaceutically acceptable acrylicpolymer, including but not limited to acrylic acid and methacrylic acidcopolymers, or an alkylcellulose such as ethylcellulose, such as acommercially-available aqueous dispersion of ethylcellulose known asAquacoat™ (FMC Corp., Philadelphia, Pa., U.S.A.). The acrylic polymer incertain instances may be one or more ammonio methacrylate copolymerscommercially available from Rohm Pharma under the Tradename Eudragit™.

To form a controlled release tablet dosage form, particles prepared asdescribed above will be admixed or blended with the desiredexcipient(s), e.g., one or more of the standard excipients such asdiluents, lubricants, binding agents, flow aids, disintegrating agents,surface active agents or water soluble polymeric materials, if any,using conventional procedures, e.g., using a Y-cone or bin-blender. Theresulting mixture may then be compressed according to conventionaltableting procedure using a suitable size tableting mold. Tablets can beproduced using conventional tableting machines, such as a standardsingle punch F3 Manesty machine or Kilian RLE15 rotary tablet machine.The tablets may be any suitable shape, such as round, oval, biconcave,hemispherical, etc.

Suitable diluents include microcrystalline cellulose, lactose anddicalcium phosphate. Suitable lubricants are e.g. magnesium stearate andsodium stearyl fumarate. Suitable binding agents are, e.g.,hydroxypropyl methyl cellulose, polyvidone and methyl cellulose.

Suitable disintegrating agents include starch, sodium starch glycolate,crospovidone and croscarmalose sodium. Suitable surface active agentsinclude Poloxamer 188R, Polysorbate 80 and sodium lauryl sulfate.Suitable flow aids include talc colloidal anhydrous silica. Suitablewater soluble polymers include polyethylene glycol (“PEG”) withmolecular weights in the range 1000 to 6000.

Generally, even with a highly water soluble active agent as tramadol,tablets formed by compression according to standard methods give verylow in vitro release rates of the active ingredient e.g. correspondingto release over a period of greater than 24 hours and, in certainembodiments, more than 36 hours. However, suitable selection of thematerials used in forming the particles and in the tableting and theproportions in which they are used enables a significant degree ofcontrol in the ultimate dissolution and release rates of the tramadol orsalt thereof from the compressed tablets. For instance a higher loadingof the drug will typically be associated with increased release rates;the use of larger proportions of water soluble fusible materials in theparticles or surface active agent in the tableting formulation will alsobe associated with a higher release rate of the active ingredient. Bycontrolling the relative amounts of these ingredients it is possible toadjust the release profile of the tramadol.

In certain embodiments, the controlled release tramadol dosage formsused in the present invention may be prepared in a manner that providesstability. The dosage form may be cured to an endpoint at which thedosage form provides a reproducible stable dissolution profile, evenafter exposure to accelerated storage conditions or after prolongedstorage at room temperature. The dosage form may be cured by exposure toprolonged elevated temperatures in order to achieve stability. Insituations where the hydrophobic material includes only a wax-likesubstance, the curing may be accomplished at a temperature from about35° C. to about 65° C., for a sufficient time period until stability isachieved, such as for a time period from about 4 to about 72 hours. Inother embodiments, the curing is conducted at a temperature from about40° C. to about 60° C., for a time period from about 5 to about 48hours, preferably at least about 24 hours. Suitable curing times whichachieve the intended result of a stabilized dosage form are known tothose of skill in the art.

The curing endpoint may be determined by comparing the dissolutionprofile of the cured dosage form immediately after curing (hereinafterreferred to as “the initial dissolution profile”) to the dissolutionprofile of the dosage form after exposure to accelerated storageconditions or prolonged storage at room temperature. Generally, thecuring endpoint may be determined by comparing the dissolution profileof the formulation after exposure to accelerated storage conditions of,e.g., 37° C./80% RH or 40° C./75% RH for a time period of one month tothe initial dissolution profile. However, the curing endpoint may befurther confirmed by continuing to expose the cured, coated formulationto accelerated storage conditions for a further period of time andcomparing the dissolution profile of the formulation after furtherexposure of, e.g., two months and/or three months, to the initialdissolution profile obtained.

In certain embodiments, the curing endpoint is attained when the datapoints plotted along a graph of the dissolution curve obtained after,e.g., exposure to accelerated conditions of 1-3 months, show a releaseof the active agent (tramadol) which does not vary at any given timepoint by more than about 20% of the total amount of active agentreleased when compared to in vitro dissolution conducted prior tostorage. Such a difference in the in vitro dissolution curves isreferred to in the art as a “band range” or a “band width”. In certainembodiments, the band range may be less than 10% to 15% of the totalamount of active agent released.

A generally accepted accelerated test employed according to FDAguidelines relates to the storage of a drug product (e.g., in itscontainer and package) at 80% Relative Humidity (RH) and 37° C. (1985FDA guidelines). If the product holds up for, e.g., three months underthese conditions (chemical stability, dissolution, and physicalcharacteristics), then the drug product will be accorded, e.g., a twoyear expiration date. This accelerated test may also be conducted at 75%RH and 40° C. It has been proposed that long-term storage testing beconducted for pharmaceutical formulations at 25° C.+/−2° C. at not lessthan 60% RH+/−5% for a minimum time period of 12 months. It has beenfurther proposed that accelerated testing be conducted forpharmaceutical formulations at 40° C.+/−2° C. at 75% RH+/−5% for aminimum time period of 6 months. All of the above-mentioned acceleratedtesting criteria and others are deemed equivalent for purposes of thepresent invention, with regard to the determination of stability and thedetermination of the curing endpoint.

7. EXAMPLES 7.1 Example 1

Controlled release tramadol hydrochloride formulations were developedfor the relief of mild to moderate pain by administration once a day, toreduce the frequency of dosing. A clinical study, as described below,was conducted using the following products.

I. Controlled Release Tramadol Dosage Forms

A) 200 mg Tramadol HCl-Controlled Release Tablet

Ingredients Mg/Tablet Tramadol HCl 200.0 Ethocel Std 7 Premium 74.0Stearyl alcohol 74.0 Talc (lubricant) 7.4 Magnesium stearate (lubricant)3.7 Total 359.1

The tablets are further coated with 4.5% Opadry Beige dispersed inwater.

Controlled release tramadol oral tablets were made according to theabove formulation utilizing the following process:

-   1. Blend all ingredients except for lubricants in a V-blender.-   2. Place the mixture in a powder feeder connected to a Leistritz    ZSE-27 twin screw extruder having multiple heating zones.-   3. Set the temperatures of the extruder heating zones 2 through 6 to    70° C., zones 7 and 8 to 75° C., zones 9 and 10 to 85° C., and the    die to 100° C.-   4. Set the extruder screw rotation speed to 200 rpm.-   5. Start the feeder and conveyor.-   6. After the excipients are melted and the drug is embedded in the    molten mixture, the viscous mass is extruded into multiple strands    of about 3 mm in diameter.-   7. Allow the extrudate to congeal and harden while being carried    away on a conveyor belt.-   8. Break the extrudate into rods of about one inch in length using a    pelletizer.-   9. Mill the extrudate using a Fitzmill.-   10. Lubricate the sized extrudate with required amounts of magnesium    stearate and talc by blending in a V-blender.-   11. Compress the lubricated blend into tablets using a tablet press    equipped with suitable tooling. In this example, the THCR dosage    form made was a 200 mg tablet having a size of 0.2320″×0.5720″    having an indented line bisecting each side.-   12. Cure the tablets at 50° C. for 24 hours in a Hotpack oven.-   13. Coat the tablets with Opadry dispersed in water using a Compulab    Coater equipped with a 48 inch pan.

In vitro measurements of the tramadol HCl controlled release tabletswere conducted using the following dissolution method (No. 340-DS1-1AS):

-   1. Apparatus—USP Type II (Paddle), 100 RPM-   2. Medium—900 ml 55 mM potassium phosphate buffer, pH 6.5, (37° C.-   3. Sampling time—2, 8, 24 hours-   4. Analytical test—High Performance Liquid Chromatography using    Waters Symmetry C-18 column and UV detection at 270 nm.

Dissolution Results for THCR 200 Time (hr) % Dissolved 2 27 8 52 24 82B) 100 mg Tramadol HCl-Controlled Release DosageManufacturing Process

1. Break tramadol 200 mg controlled release tablets, which were made inaccordance with above-described formulation and method, into two halvesmanually at the score.

2. Fill one half tablet into Size 0 gelatin capsules.

3. Back fill the capsule with lactose.

Dissolution Method

The dissolution test method was the same as that described above withrespect to the 200 mg tablet.

Dissolution Results

Dissolution Results for THCR 100 (capsule containing half tablet of THCR200) Time (hr) % Dissolved 2 39 8 69 24 94C) 300 mg Tramadol Controlled Release Dosage

Dosages of 300 mg tramadol controlled release tablets were provided inthe form of one 200 mg tramadol controlled release tablet, as preparedabove, and one 100 mg tramadol controlled release dosage, also asprepared above.

II. Clinical Study and Results

The effect of various dose titration schedules of tramadol hydrochloridecontrolled release tablets was studied in a multiple-dose, randomized,double-blind, parallel group, placebo-controlled, multi-center,outpatient study. A total of two hundred five (205) male subjectsenrolled in the study and were randomly assigned into one of fourtreatment groups. The planned total number of evaluable subjects was200, with 50 subjects in each treatment group. Treatment groups weretitrated over a dosing period lasting 21 days at three different ratesto achieve the study target dose of 300 mg/day: the “THCR 100 Group”followed a 100_(Day 1-7) to 200_(Day 8-14) to 300_(Day 15-21) mg q.d.dosing regimen; the “THCR 200 group” followed a 200_(Day 1-7) to300_(Day 8-14) to 300_(Day 15-21) mg q.d. dosing regimen; and the “THCR300 group” followed a 300_(Day 1-7) to 300_(Day 8-14) to300_(mg q.d. Day 15-21) mg q.d. dosing regimen. The fourth groupreceived placebos during the course of the study. Study medication orplacebo was always administered once per day or q.d. One hundredninety-three (193) subjects completed the study. Observed adverse eventswere assessed. As used herein, an adverse event or side effect includesany noxious, pathologic, or unintended change in anatomical,physiological, or metabolic functions as indicated by physical signs,symptoms, or laboratory changes occurring in any phase of the clinicalstudy, whether or not considered drug-related.

All study medication was packaged in bottles to be dispensed to thesubjects on a weekly basis. All subjects were given two bottles weekly:bottle A, containing THCR 200 mg tablets or matching placebo tablets;and bottle B, containing encapsulated half-tablet (100 mg) THCR 200 mgtablets or matching placebo capsules. Each participant was givendetailed instructions on how to take the study medication. Specifically,each participant was directed to take one tablet from bottle A and onecapsule from bottle B by mouth at 8:00 am (+/−2 hours). The treatmentgroup which a participant belonged to determined whether the tabletsand/or capsules in the participant's bottles contained THCR or placebo.

As shown in Table 1, entitled “Mean Severity of Tramadol-like andDistractor-Elicited Side Effects”, the study results showed that thetitration dosage regimen of controlled release tramadol in accordancewith the instant invention, as seen in the THCR 100 Group (100_(Day 1-7)to 200_(Day 8-14) to 300_(Day 15-21) mg q.d.) and in the THCR 200 Group(200_(Day 1-7) to 300_(Day 8-14) to 300_(Day 15-21) each mg q.d.)treatment groups, resulted in statistically significant lower meanseverity of adverse tramadol elicited side effects than in the THCR 300Group (300_(Day 1-7) to 300_(Day 8-14) to 300 Day₁₅₋₂₁ mg q.d.),particularly for the THCR 100 Group during days 1 to 14 and for the THCR200 Group for days 1 to 7, when the mean severity of the noted adverseeffects did not exceed those of the placebo group in a statisticallysignificant manner.

More specifically, whenever subjects were administered 300 mg q.d. THCR(the THCR 100 Group, for days 15 to 21; the THCR 200 Group, for days 8to 14 and 15 to 21; and the THCR 300 Group, for all 3 periods), thedifference of the mean severity of elicited side effects (particularlywith respect to the most common side effect of nausea) was significantcompared to the placebo group. Thus, starting with THCR 100 mg q.d. or200 mg q.d. was similar to placebo and well tolerated. However, startingwith THCR 300 mg q.d. was distinct in terms of side effects from theother week 1 doses, and was not as well tolerated. In fact, as shown inTable 2, entitled “Tolerability Over All 21 Days”, a higher incidence ofnausea, constipation, dizziness and pruritus occurred in the THCR 300Group compared with the THCR 200 Group and the THCR 100 Group.

TABLE 1 Mean Severity of Tramadol-like and Distractor-Elicited SideEffects Days 1-7 Days 8-14 Days 15-21 Overall Placebo (N = 49)Tramadol-like side effects Mean ± SEM .17 ± .035 .13 ± .027 .11 ± .023.138 ± .0218 Distractor side effects Mean ± SEM .09 ± .040 .05 ± .015.03 ± .015 .061 ± .0179 THCR 100 (N = 47) Group (100/200/300)Tramadol-like side effects Mean ± SEM .28 ± .035 .22 ± .033 .29 ^(a) ±.040   .258 ^(a) ± .0283   Distractor side effects Mean ± SEM .10 ± .021.05 ± .013 .08 ± .017 .077 ± .0132 THCR 200 (N = 48) Group (200/300/300)Tramadol-like side effects Mean ± SEM .29 ± .045 .31 ^(a) ± .046   .25^(a) ± .039   .287 ^(a) ± .0382   Distractor side effects Mean ± SEM .05± .014 .06 ± .019 .05 ± .017 .053 ± .0120 THCR 300 (N = 49) Group(300/300/300) Tramadol-like side effects Mean ± SEM .43 ^(a,b,c) ± .056   .30 ^(a) ± .036   .28 ^(a) ± .042   .337 ^(a) ± .0367   Distractorside effects Mean ± SEM .10 ± .025 .08 ± .015 .08 ± .019 .084 ± .0149Treatment comparisons * (tramadol-like) s s s s Treatment comparisons *(distractor) ns ns ns ns Severity was assessed on a numerical scale: 0 =none; 1 = mild; 2 = moderate; 3 = severe; 4 = intolerable. The meanseverity of the 7 tramadol-like elicited side effects was pooled. Themean severity of the 7 distractor-elicited side effects was pooled.These were then assessed for the 3 treatment periods and overall 21 daysof the study. Boldface indicates statistical significance. ^(a)=significance compared to placebo; ^(b)= significance compared to THCR100 mg q.d.; ^(c)= significance compared to THCR 200 mg q.d. Pair-wisecomparisons were derived from Fisher's LSD. * Overall treatmentcomparison used ANOVA. ns = nonsignificance; s = significance

TABLE 2 Tolerability Over All 21 Days Group Mean Scores Effect Size^(a)THCR THCR THCR Pooled SD (p Value)^(b) Placebo 100 Group 200 Group 300Group THCR 100 THCR 200 THCR 300 Parameter (PBO) (100/200/300)(200/300/300) (300/300/300) SD (100/200/300) (200/300/300) (300/300/300)DOAR 0 0 0 0 0 0 0 0 Spontaneously 1.78 3.28 3.33 4.39 3.14 0.48 0.500.83 reported (.0202) (.0156) (<.0001) adverse events Overall 0.33 0.530.49 0.59 0.47 0.42 0.35 0.55 subjective (0.478) (.0935) (.0077)side-effect experience^(c) Combined 7 0.14 0.26 0.29 0.34 0.22 0.54 0.670.90 tramadol- (.0106) (.0013) (<.0001) like side effects^(c) Combined 70.06 0.08 0.05 0.08 0.10 0.16 −0.08 0.22 distractor- (.4442) (.6974)(.2724) elicited side effects^(c) Elicited 0.07 0.15 0.21 0.28 0.34 0.230.41 0.62 side effect: (.266) (.0496) (.0028) nausea^(c) Elicited 0.010.10 0.10 0.08 0.24 0.36 0.36 0.28 side effect: (.086) (.0824) (.1684)vomiting^(c) Elicited 0.06 0.23 0.18 0.43 0.37 0.44 0.33 0.99 sideeffect: (.0347) (.1128) (<.0001) dizziness^(c) ^(a)= Effect sizes arecompared to placebo ^(b)= P values are derived from pairwise comparisonsof treatment groups vs placebo from the analysis of variance usingFisher's LSD. Differences are statistically significant if P < 0.0499.^(c)= Mean scores are the least squares mean severity on a 0 to 4 scale,where 0 = none, 1 = mild, 2 = moderate, 3 = severe, and 4 = intolerable.DOAR = dropout due to adverse reaction.

In summary, the titration regimen starting with doses of THCR at 100 mgq.d. or 200 mg q.d., respectively, to reach the most commonly prescribedeffective daily dose of 300 mg q.d. leads to significantly bettersubject tolerability than starting therapy with doses of 300 mg q.d.,and, surprisingly, in some cases is as well tolerated as placebo. Theuse of a titration dosing regimen according to the present invention, ascompared to a dosing regimen of 300 mg q.d. controlled release tramadolon day 1 and thereafter, exhibited significant improvements in subjecttolerability of controlled release tramadol based on starting dose andtitration schedule. For the most common side effects, there was a clearstatistically significant titration schedule response, such that theTHCR 100 Group (100_(Day 1-7) to 200_(Day 8-14) to 300_(Day 15-21))dosing regimen was superior to the THCR 200 Group (200_(Day 1-7) to200_(Day 8-14) to 300_(Day 15-21)) dosing regimen which was superior tothe THCR 300 Group (300_(Day 1-7) to 300_(Day 8-14) to 300_(Day 15-21))dosing regimen, in terms of tolerability.

7.2 Example 2

A more preferable way of formulating 100 mg tramadol HCl controlledrelease tablets is according to the following formulation:

Formula (100 mg/tablet)

Formula (100 mg/tablet) Ingredients Mg/Tablet Tramadol HCl 100.0 EthocelStd 7 Premium 41.5 Stearyl alcohol 41.5 Talc 3.8 Magnesium stearate 1.9Total 188.7

The tablets are further coated with 2.5% Opadry White dispersed inwater.

The manufacturing process is the same as that described above in Example1, with respect to THCR 200 mg tablets.

The following table sets forth dissolution data for such THCR 100 mgtablets. The dissolution method is the same as that described above inExample 1 with respect to THCR 200 mg tablets.

Dissolution Results for 100 mg tablet Time (hr) % Dissolved 2 27 8 52 2482

7.3 Example 3

A more preferable way of formulating 300 mg tramadol HCl controlledrelease tablets is to make a single 300 mg tablet as follows:

Formula (300 mg/tablet) Ingredients Mg/Tablet Tramadol HCl 300.0 EthocelStd 7 Premium 100.0 Stearyl alcohol 100.0 Talc 10.0 Magnesium stearate5.0 Total 515.0

The tablets are further coated with 4.5% Opadry Beige dispersed inwater.

The manufacturing process is the same as that described above in Example1 with respect to THCR 200 mg tablets.

The following table sets forth dissolution data for such THCR 300 mgtablets. The dissolution method is the same as that described above inExample 1 with respect to THCR 200 mg tablets.

Dissolution Results for THCR 300 Time (hr) % Dissolved 2 33 8 60 24 89

All patents, applications, publications, test methods, literature andother material cited above are hereby incorporated by reference.

We claim:
 1. A dosage regimen for administering tramadol to a patientfor the treatment of pain comprising administering: about 100 mg oftramadol in a controlled release dosage form once-a-day on days 1through 7; then about 200 mg of tramadol in a controlled release dosageform once-a-day on days 8 through 14; then about 300 mg of tramadol in acontrolled release dosage form once-a-day on day 15 and optionallythereafter.
 2. The dosage regimen of claim 1 wherein the controlledrelease dosage forms are each oral dosage forms.
 3. The dosage regimenof claim 2 wherein the tramadol is present in each oral dosage form inthe form of tramadol hydrochloride.
 4. The dosage regimen of claim 3each oral dosage form provides in vitro release of tramadolhydrochloride for about 24 hours or longer.
 5. The dosage regimen ofclaim 1 further comprising administering about 300 mg of tramadol in acontrolled release dosage form once-a-day on days 15 through 21 andoptionally thereafter.
 6. The dosage regimen of claim 5 wherein 100 mgof tramadol is administered in a controlled release dosage form on days1 through 7; 200 mg of tramadol is administered in a controlled releasedosage form on days 8 through 14; and 300 mg of tramadol is administeredin a controlled release dosage form on days 15 through 21 and optionallythereafter.
 7. The dosage regimen method of claim 6 wherein the tramadolis present in each oral dosage form in the form of tramadolhydrochloride.
 8. The dosage regimen method of claim 7 wherein each oraldosage form provides an in vitro release of tramadol hydrochloride ofabout 24 hours or more.
 9. A dosage regimen for administering tramadolto a patient for the treatment of pain comprising administering: about175 mg to about 225 mg of tramadol in a controlled release dosage formonce-a-day for about 4 to about 10 days; then about 275 mg to about 325mg of tramadol in a controlled release dosage form once-a-day for atleast 1 day and optionally thereafter.
 10. The dosage regimen of claim 9wherein the controlled release dosage forms are each oral dosage forms.11. The dosage regimen of claim 10 wherein the tramadol is present ineach oral dosage form in the form of tramadol hydrochloride.
 12. Thedosage regimen of claim 11 wherein each oral dosage form provides an invitro release of tramadol hydrochloride of about 24 hours or more. 13.The dosage regimen of claim 9 comprising administering about 275 mg toabout 325 mg of tramadol in a controlled release dosage form once-a-dayfor at least 6 days and optionally thereafter.
 14. A dosage regimen foradministering tramadol to a patient for the treatment of pain comprisingadministering: about 200 mg of tramadol in a controlled release dosageform once-a-day for days 1 through 7; then about 300 mg of tramadol in acontrolled release dosage form once-a-day for at least 1 day andoptionally thereafter.
 15. The dosage regimen of claim 14 wherein thecontrolled release dosage forms are each oral dosage forms.
 16. Thedosage regimen of claim 15 wherein the tramadol is present in each oraldosage form in the form of tramadol hydrochloride.
 17. The dosageregimen of claim 16 wherein each oral dosage form provides an in vitrorelease of tramadol hydrochloride of about 24 hours or more.
 18. Thedosage regimen of claim 14 comprising administering about 300 mg oftramadol in a controlled release dosage form once-a-day for at least 7days and optionally thereafter.
 19. A kit for the administration of adosage regimen of tramadol comprising: instructions to administer thefollowing amounts of tramadol in controlled release oral dosage formsaccording to the following dosage regimen: 100 mg of tramadol once-a-dayon days 1 through 7; 200 mg of tramadol once-a-day on about days 8through 14; and 300 mg of tramadol once-a-day on about days 15 through21, and optionally thereafter; and a sufficient quantity of controlledrelease oral dosage forms of tramadol to administer tramadol accordingto the dosage regimen.
 20. A kit for the administration of a dosageregimen of tramadol comprising: instructions to administer the followingamounts of tramadol in controlled release oral dosage forms according tothe following dosage regimen: 200 mg of tramadol once-a-day on days 1through 7; and 300 mg of tramadol once-a-day on about days 8 through 14,and optionally thereafter; and a sufficient quantity of controlledrelease oral dosage forms of tramadol to administer tramadol accordingto the dosage regimen.